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TAVI intermediate risk:
Reality or passion?
Prof. Flavio Ribichini
Università di Verona
Italy
TAVI vs Surgical AVR for Moderate to Low
Risk Patients
Reality
Prof. Flavio Ribichini
Università di Verona
Italy
TAVI vs Surgical AVR for Moderate to Low
Risk Patients
Thyregod HG et al JACC 2015
- RCT involving 280 pts in 3 Nordic Centers, 1:1 TAVI vs SAVR
- Esclusion Criteria: severe valve (other than aortic) disease, CAD requiring intervention, previous cardiac surgery, MI, stroke (within 30 days), severe renal failure requiring dialysis, pulmonary failure.
- Primary Endpoint: composite rate of all-cause death, stroke or MI at 1 year FU.
- Only self-explandable (CoreValve) and valve sizing by means of EchoTOE
NOTION Trial
NOTION Trial Intention-to-treat analysis: the composite rate of death from any cause, stroke, orMI at 1 year (the primary outcome) was similar in the 2 groups: 13.1% vs. 16.3% for TAVR and SAVR (-3.2% absolute difference; p = 0.43 for superiority)
NOTION Trial
Primary Endpoint: All-Cause Mortality or Disabling Stroke at Two Years
Randomized Patients
n = 2032
Symptomatic Severe Aortic Stenosis
ASSESSMENT by Heart Valve Team
Operable (STS ≥ 4%)
The PARTNER 2A Trial Study Design
TF TAVR
(n = 775)
Surgical AVR
(n = 775) VS. VS.
ASSESSMENT:
Transfemoral Access
Transapical (TA) / TransAortic (TAo) Transfemoral (TF)
1:1 Randomization (n = 482) 1:1 Randomization (n = 1550)
TA/TAo TAVR
(n = 236) Surgical AVR
(n = 246)
Yes No
Key Exclusion Criteria
• Aortic annulus diameter < 18 mm or > 27 mm (echo or CT)
• Bicuspid AV or predominant AR (> 3+)
• Severe LV dysfunction (LVEF < 20%)
• Untreated CAD requiring revascularization with either unprotected LM coronary disease or Syntax score > 32
• Pre-existing surgical valve in any position
Anatomic:
• Serum Cr > 3.0 mg/dL or dialysis dependent
• Acute MI within 1 month
• CVA or TIA within 6 months
• Hemodynamic instability
• Life expectancy < 24 months
Clinical:
Characteristic TAVR
(n = 1011)
Surgery
(n = 1021) p-value
Age - yrs 81.5 ± 6.7 81.7 ± 6.7 0.63
Male - % 54.2 54.8 0.79
STS Score - % 5.8 ± 2.1 5.8 ± 1.9 0.29
NYHA Class III or IV - % 77.3 76.1 0.53
CAD - % 69.2 66.5 0.20
Prior CABG - % 23.6 25.6 0.33
Cerebrovascular Disease - % 32.1 31.0 0.60
PVD - % 27.9 32.9 0.02
Baseline Patient Characteristics Demographics and Vascular Disease
Characteristic (%) TAVR
(n = 1011)
Surgery
(n = 1021) p-value
Diabetes 37.7 34.2 0.11
COPD - Any 31.8 30.0 0.48
O2 dependent 3.4 3.1 0.64
Creatinine > 2 mg/dL 5.0 5.2 0.92
Atrial Fibrillation 31.0 35.2 0.05
Permanent Pacemaker 11.7 12.0 0.84
Frailty (15 ft walk > 7 s) 44.4 46.4 0.43
Liver Disease 1.9 2.5 0.37
Baseline Patient Characteristics Other Co-morbidities
1
1011 918 901 870 842 825 811 801 774
1021 838 812 783 770 747 735 717 695
Number at risk:
TAVR
Surgery
p (log rank) = 0.253
HR [95% CI] = 0.89 [0.73, 1.09]
TAVR
Surgery
0
10
20
30
40
50
19.3%
21.1%
14.5%
16.4%
0 3 6 9 12 15 18 21 24
6.1%
8.0%
Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke
Months from Procedure
All
-Cau
se M
ort
ality
or
Dis
ab
lin
g S
tro
ke (
%)
1
775 718 709 685 663 652 644 634 612
775 643 628 604 595 577 569 557 538
TF TAVR
TF Surgery
p (log rank) = 0.05
HR: 0.79 [95% CI: 0.62, 1.00]
16.8%
20.4%
0 3 6 9 12 15 18 21 24
0
10
20
30
40
50
15.9%
7.7%
12.3%
4.9%
TF Primary Endpoint (ITT) All-cause Mortality or Disabling Stroke
TF TAVR
TF Surgery
Months from Procedure Number at risk:
All
-Cau
se M
ort
ality
or
Dis
ab
lin
g S
tro
ke (
%)
The PARTNER 2A Trial Conclusions
In intermediate-risk patients with symptomatic severe
aortic stenosis, results from the PARTNER 2A trial
demonstrated that...
• TAVR using SAPIEN XT and surgery were similar
(non-inferior) for the primary endpoint (all-cause mortality
or disabling stroke) at 2 years.
• In the transfemoral subgroup (76% of patients), TAVR
using SAPIEN XT significantly reduced all-cause
mortality or disabling stroke vs. surgery (ITT: p = 0.05,
AT: p = 0.04).
Intermediate Surgical Risk Predicted risk of operative mortality ≥3% and <15%
Heart Team Evaluation Assess inclusion/exclusion
Risk classification
Randomization Stratified by need for revascularization
TAVR SAVR
TAVR + PCI SAVR + CABG TAVR only SAVR only
Baseline neurological assessments
Screening Committee Confirmed eligibility
SURTAVI Trial Design
First patient enrolled June 19, 2012
Primary endpoint assessment
Dec 2016
CoreValve (n=724) Evolut R (n=139)
2012 2013 2014 2015 2016
Enrollment completed June 30, 2016
Evolut R (US)
CoreValve: 23, 26 and 29 mm (CAN, EU)
CoreValve: 31 mm (US, CAN, EU)
94% TF 4% DA 2% SCA
CoreValve: 23, 26 and 29 mm (US)
April
Study Timeline
• Contraindication for placement of a bioprosthetic valve • A known hypersensitivity or contraindication to all anticoagulation/
antiplatelet regimens • Any PCI or peripheral intervention within 30 days of randomization • Symptomatic carotid or vertebral artery disease or successful treatment of
carotid stenosis within six weeks of randomization • Recent cerebrovascular accident or transient ischemic attack • Acute MI within 30 days • Multivessel CAD with Syntax score >22 • Severe liver, lung or renal disease • Unsuitable anatomy including native aortic annulus <18 mm or >29 mm • Severe mitral or tricuspid regurgitation • Congenital bicuspid or unicuspid valve verified by echo
Key Exclusion Criteria
n (%) or mean ± SD TAVR (N=864) SAVR (N=796)
Age, years 79.9 ± 6.2 79.7 ± 6.1
Male sex 498 (57.6) 438 (55.0)
Body surface area, m2 1.9 ± 0.2 1.9 ± 0.2
STS PROM, % 4.4 ± 1.5 4.5 ± 1.6
Logistic EuroSCORE, % 11.9 ± 7.6 11.6 ± 8.0
Diabetes mellitus 295 (34.1) 277 (34.8)
Serum creatinine >2 mg/dl 14 (1.6) 17 (2.1)
Prior stroke 57 (6.6) 57 (7.2)
Prior TIA 58 (6.7) 46 (5.8)
Peripheral vascular disease 266 (30.8) 238 (29.9)
Permanent pacemaker 84 (9.7) 72 (9.0)
Baseline Characteristics*
*mITT population; no significant difference in any baseline characteristics
n (%) TAVR (N=864) SAVR (N=796)
Coronary artery disease 541 (62.6) 511 (64.2)
Prior CABG 138 (16.0) 137 (17.2)
Prior PCI 184 (21.3) 169 (21.2)
Prior myocardial infarction 125 (14.5) 111 (13.9)
Congestive heart failure 824 (95.4) 769 (96.6)
History of arrhythmia 275 (31.8) 250 (31.4)
Atrial fibrillation 243 (28.1) 211 (26.5)
NYHA Class III/IV 520 (60.2) 463 (58.2)
Baseline Cardiac Risk Factors*
*mITT population; no significant difference in any baseline characteristics
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
All-
Cau
se M
ort
alit
y o
r D
isab
ling
Stro
ke
Months Post-Procedure No. at Risk
796 674 555 407 241
864 755 612 456 272 TAVR
SAVR
All-Cause Mortality or Disabling Stroke
24 Months
TAVR SAVR
12.6% 14.0%
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
All-
Cau
se M
ort
alit
y
Months Post-Procedure No. at Risk
796 690 569 414 249
864 762 621 465 280 TAVR
SAVR
All-Cause Mortality
30 Day SAVR 1.7% O:E 0.38 TAVR 2.2% O:E 0.50
TAVR
SAVR
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
24 Months
TAVR
SAVR 95% CI for Difference
11.4% 11.6% -3.8, 3.3
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
All-
Cau
se M
ort
alit
y
Months Post-Procedure
TAVR
SAVR
No. at Risk 796 690 569 414 249
864 762 621 465 280 TAVR
SAVR
All-Cause Mortality
30 Day SAVR 1.7% O:E 0.38 TAVR 2.2% O:E 0.50
0%
2%
4%
6%
8%
10%
0 6 12 18 24
Dis
ablin
g St
roke
Months Post-Procedure No. at Risk
796 674 555 407 241
864 755 612 456 272 TAVR
SAVR
Disabling Stroke
24 Months
TAVR SAVR 95% CI for Difference
2.6% 4.5% -4.0, 0.1
• TAVR had significantly less 30 day stroke, AKI, atrial fibrillation and transfusion use and a superior quality of life at 30 days.
• SAVR had less residual aortic regurgitation, major vascular complications and fewer new pacemakers.
• Need for a new pacemaker after TAVR was not associated with increased mortality.
Summary
• SURTAVI met its primary endpoint demonstrating that TAVR with a self-expanding CoreValve or Evolut R bioprosthesis is noninferior to SAVR for all-cause mortality or disabling stroke at 24 months.
Guidelines AHA/ACC Update 2017
1. The research of the optimal anti-thrombotic therapy 2. Valve performance at long-term 3. Indications: low surgical risk? 4. What remains for surgical AVR and conservative management
TAVI intermediate risk:
Reality or passion?
1. TAVI, valve thrombosis and the ideal therapy
- Study investigating the use of CT scan to reveal «subclinical leaflet thrombosis» by finding a reduced leaflet motion in patients who underwent TAVI.
- Data obtained from the Portico IDE Trial and Resolve and Savory registries.
- Reduced leaf let motion was noted on CT in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries.
- Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaf let motion (0% and 55%, respectively, P=0.01 in the clinical trial; and 0% and 29%, respectively, P=0.04 in the pooled registries.
Makkar RR et al NEJM 2015
Volume rendered CT images of bioprosthetic valves
Normal leaflets Thickened leaflets with thrombus
Systole Systole
Diastole Diastole
Makkar R. et al. NEJM 2015
Study Objectives
To study subclinical leaflet thrombosis of
bioprosthetic aortic valves in terms of
• Prevalence in a large heterogenous cohort of patients
• Differences in TAVR and SAVR
• Impact of novel-oral anticoagulants (NOACs)
• Impact on valve hemodynamics
• Impact on clinical outcomes
Study design
890 patients with interpretable CTs were included in the
analysis
RESOLVE registry:
626patients
SAVORY registry:
264 patients
931 patients undergoing CTs
657 patients underwent CTs in
the RESOLVE registry Cedars-Sinai Medical Center, Los Angeles
274 patients underwent CTs in
the SAVORY registry Rigshospitalet, Copenhagen
Valve types and timing of CT Time from TAVR to CT vs. SAVR to CT: p<0.0001
890 patients with interpretable CTs
Median time from AVR to CT 83 days (IQR 32-281 days)
752 transcatheter valves
Median time from TAVR to
CT 58 days (IQR 32–236
days)
138 surgical valves
Median time from SAVR to
CT 162 days (IQR 79–417
days)
Reduced leaflet motion of at least 50% in
multiple valve types
Sapien Evolut R Lotus Portico Centera Symetis Perimount Magna
Prevalence of reduced leaflet motion
Transcatheter vs. surgical bioprosthetic aortic valves: p=0.001
Reduced leaflet motion was present in 106
(11.9%) patients
Transcatheter valves
13.4% (101 out of 752)
Surgical valves
3.6% (5 out of 138)
Anticoagulation and reduced leaflet
motion Anticoagulation vs. no anticoagulation
0.
0
2.
0
4.
0
6.
0
10.
0
8.0
12.
0
14.
0
16.
0
Pre
va
len
ce
of
red
uc
ed
leafl
et
mo
tio
n
Anticoagulation NOACs Warfarin No
anticoagulation
8/224
(3.6%) 3/107
(2.8%)
5/117
(4.3%)
98/666
(14.7%) Anticoagulation vs. no anticoagulation: p<0.0001
NOACs vs. no anticoagulation: p=0.0002
Warfarin vs. no anticoagulation: p=0.001 NOACs
vs. warfarin: p=0.72
Anticoagulation and reduced leaflet motion Anticoagulation vs. antiplatelet therapy
4.
0
10.
0
8.0
6.0
12.
0
14.
0
16.
0
18.
0
Pre
va
len
ce
of
red
uc
ed
leafl
et
mo
tio
n
2.0
0.0
Anticoagulation NOACs Warfarin DAPT
8/224
(3.6%) 3/10
7 (2.8%)
5/117
(4.3%)
31/208
(14.9%) Anticoagulation vs. DAPT: p<0.0001
Anticoagulation vs. monoantiplatelet
therapy: p<0.0001
63/405
(15.6%)
Monoantiplatelet
therapy
Impact of initiation of anticoagulation on reduced leaflet motion
0.0
20.0
40.0
60.0
80.0
100.0
120.
0
Pre
va
len
ce
of
red
uce
d le
afl
et
mo
tio
n
Resolution
36/36
(100%
)
• Resolution in 36
out of 36 patients
treated with
anticoagulation
(NOACs, n=12;
warfarin, n=24)
• Persistence/progres
sion in 20 out of 22
patients not treated
with anticoagulation
P<0.0001
No change or
progression Resolution No change or
progression
0/36
(0%)
2/22
(9.1%)
20/22
(89.1%)
Anticoagulation initiated No anticoagulation initiated
Anticoagulation vs. DAPT
Index CT Follow-up CT
DAPT
continued after
index CT
Warfarin
initiated after
index CT
Rivaroxaban
initiated after
index CT
Apixaban
initiated after
index CT
Progression of reduced leaflet motion
Resolution of reduced leaflet motion
Resolution of reduced leaflet motion
Resolution of reduced leaflet motion
Impact of reduced leaflet motion on clinical outcomes
All clinical events post-TAVR/SAVR included
TIA=Transient ischemic attack
* All strokes include hemorrhagic and ischemic
strokes
No significant difference in strokes; but increased risk of TIAs and
strokes/TIAs
All events
Normal leaflet motion (N=784)
n/N (%) Rate per
100
person-
years
Reduced leaflet motion (N=106)
n/N (%) Rate per
100 person-
years
Hazard
ratio
(95% CI)
p-value
Death 34/784 (4·3%) 2· 91 4/106 (3·8%) 2· 66 0· 96 (0· 34-2· 72) 0· 94
Myocardial infarction 4/784 (0· 5%) 0· 34 1/106 (0· 9%) 0· 67 1· 91 (0· 21-17·08) 0· 56
Strokes/TIAs 27/784 (3·4%) 2· 36 11/106 (10·4%) 7· 85 3· 27 (1· 62-6· 59) 0· 001
All strokes* 22/784 (2·8%)
1· 92 6/106 (5·7%) 4· 12 2· 13 (0· 86-5· 25)
0· 10
Ischemic strokes 21/784 (2·7%) 1· 83 6/106 (5·7%) 4· 12 2· 23 (0· 90-5· 53) 0· 08
TIAs 7/784 (0·9%) 0· 60 6/106 (5·7%) 4· 18 7· 02 (2· 35-20· 91) 0· 0005
2. TCVT performance at long-term
PARTNER 1 - Echocardiographic data
Valve Area
PARTNER 1 - Echocardiographic data
Valve Gradient
Four-year experience with the CoreValve
transcatheter heart valve
Four-year experience with the CoreValve
transcatheter heart valve
First look at long-term durability of
transcatheter heart valves: Assessment of valve function up to
10-years after implantation
Danny Dvir, St. Paul’s Hospital, Vancouver, Canada.
On behalf of coauthors: Helene Eltchaninoff, Jian Ye, Arohumam Kan, Eric Durand, Anna Bizios, Anson Cheung, Mina Aziz, Matheus Simonato, Christophe Tron, Yaron Arbel, Robert Moss, Jonathon Leipsic, Hadas Ofek, Gidon Perlman, Marco Barbanti, Michael A. Seidman, Philippe Blanke, Robert Yao, Robert Boone, Sandra Lauck, Sam Lichtenstein, David Wood, Alain Cribier, John Webb
• Time to degeneration: median of 61months (IQR 36-79months).
• Degenerated valves:
Cribier Edwards (n=3, 8.6%)
Edwards SAPIEN (n=19, 54.3%)
SAPIEN XT (n=13, 37.1%)
Degenerated THV
(n = 35)
Regurgitation
(n = 23)
Stenosis/Mixed
(n = 12)
THV degeneration
Pathological examinations
Severely calcified valve 2.5 years after TAVI
Pathological examinations
Asymmetric degeneration 5 years after TAVI
Pathological examinations
Symmetric degeneration 7 years after TAVI
Freedom from THV degeneration
Patients WITHOUT chronic renal failure
Freedom from THV degeneration
Patients WITHOUT chronic renal failure
Patients WITH chronic renal failure p= 0.004
3. TAVI for patients at LOW RISK ?
We do not have reliable data yet…
Circ Cardiovasc Interv. 2016
- Observational, prospective multicenter study;
- Consecutive pts entolled in 93 centers (between Dec2010 - Jun2012)
- Low risk pts defined as Logistic Euroscore II <4%.
- Primary Endpoint: 3-years survival; Secondary endpoint: 30-day mortality, in-hospital adverse events (stroke, vascular complications, severe bleeding and AKI)
- Both self-explandable (CoreValve) & balloon-expandable (Sapien XT)
Baseline Clinical Characteristics of Propensity Score–Matched Pairs of Patients With EuroSCORE II <4%
OBSERVANT LOW-RISK
OBSERVANT LOW-RISK
Primary Endpoint
SAVR: 83.4%
TAVI: 72%
p<0.001
OBSERVANT LOW-RISK
Three-years freedom from MACCEs
SAVR: 80.9%
TAVI: 67.3%
p<0.001
4. The risk evaluation “gap”
1) Definition of “intermediate risk” patients and understanding the concept of “frailty”
2) Who may rather be a surgical candiadate
3) When TAVI is “futile”
Who is an Intermediate-risk patient?
INTERMEDIATE RISK STS score: between 4% and 8%
Logistic EuroScore I <8% Logistic EuroScore II <4%
Consider SAVR Consider TAVI
Age >80 Previous CABG or Surgical Valve intervention (Re
do)
CAD requiring intervention Bicuspid valve
Age 75-79….? Age <75
Neoplasia (survival >2y)
Low weight-Obesity Moderate-severe CKD
Intellectual Impairment Female Sex/Fraility
Small annulus/miss-match
Syntax Score >23 Syntax Score <23
Frailty not defined
Frailty, disability and comorbidity accoridng to the Deficit Index
Comorbidity
Disability
Frailty
Rockwood K et al, CMAJ 2005
Fraility, disability and comorbidity according to the Phenotype Frailty Index
Dysability (n=67)
Comorbidity (n=2131)
Fraility 26.6% (n=98)
(n=196)
5.7% (n=21)
46.2% (n=170)
21.5% (n=79)
Fried L, et al. J Gerontol 2001
COPD CKD PAD Diabetes CAD Low EF%
Intellectual impairment Arthrosis Orthopedic prosthesis Multiple slerosis Previous stroke
Advanced age Sarcopenia Osteopeoporosis Low body weight Chronic anemia
These are not the same thing…
How to define “fraility” : The Canadian Cardiovascular Health Study
Fried L, et al. J Gerontol 2001
1. Handgrip inferior quintile
2. Gait speed in the inferior quintile
3. Spontaneous weight loos ≥4,5 kg in the last year
4. Easy exhaustibility
5. Physical activity in the inferior quartile
PHENOTYPE FRAILTY INDEX
Frail: ≥3 components
Intermediate (pre-frail): 1 o 2 components
Non frail (robust): 0 component
Short Physical Performance Battery (SPPB)
Test della marcia
Tempo per percorrere 4 metri
di passo normale: ____sec
(tempo migliore di 2 prove)
<4.8 sec 4 punti
4.8-6.2 sec 3 punti
6.3-8.7 sec 2 punti
>8.7 sec 1 punto
incapace 0 punti
0 1 2 3 4 m
Capace
Alzarsi e sedersi per 5 volte più
velocemente possibile a braccia
incrociate
<11.2 sec 4 punti
11.2-13.7 sec 3 punti
13.8-16.7 sec 2 punti
16.8-60 sec 1 punto
>60 sec o incapace 0 punti
Test della sedia
Punteggio totale:
0-12
Guralnik et al, J Gerontol 1994
Posizione piedi uniti
per 10 sec 1 punto
Posizione
semitandem
per 10 sec 1 punto
Posizione tandem
tempo:____ sec
per 10 sec 2 punti
3-9.9 sec 1 punto
<3 sec 0 punti
tempo:____ sec
<10 secondi 0 punti
tempo:____ sec
<10 secondi 0 punti
Test dell’equilibrio
SI
SI
NO
NO
Prognostic value of the SPPB in the aged population
Mobility disability
Non-disabled
BADL disability
%
SPPB score 4 5 6 7 8 9 10 11 12
100
80
60
40
20
0
N= 1122, FU 4 yrs.
Guralnik J, et al. N Engl J Med 1995
The Italian Ministry of Health suggests the introduction in clinical practice of the Short Physical Performance Battery (SPPB) (2013)
2 A
ño
s
4 A
ño
s
12
Añ
os
18
Añ
os
20
Añ
os
35
Añ
os
50
Añ
os
60
Añ
os
70
Añ
os
75
Añ
os
80
Añ
os
90
Añ
os
Poder caminar
No orinarse encima
Tener amigos
Poder conducir
Poder hacer sexo
Ganar dinero
Parabola vital: poque NO hay que tratar a los ancianos de manera diferente a los jòvenes...